Clinicopathological and molecular features of hereditary leiomyomatosis and renal cell cancer-associated renal cell carcinomas

Abstract

AimsHereditary leiomyomatosis and renal cell cancer (HLRCC) is an autosomal dominant disorder caused by germline mutations in fumarate hydratase (FH). Affected families have an increased risk of renal cell carcinoma (RCC). HLRCC-associated RCC (HLRCC-RCC) is highly aggressive. Clinicopathological information of genetically diagnosed patients with HLRCC-RCC contributes to the establishment of effective therapies.MethodsTen Japanese patients with HLRCC-RCC were enrolled in the study. Genetic testing for FH was carried out. Somatic mutations in FH and immunohistochemical analyses of FH and B7 family ligands (PD-L1 and B7-H3) were investigated in 13 tumours. Copy number variations were evaluated in two tumours.ResultsAll patients had FH germline mutations. Regarding histology, most tumours had type 2 papillary architecture or tubulocystic pattern or both. All tumours were FH deficient by immunohistochemistry. Ten tumours were positive for PD-L1, and 12 tumours were positive for B7-H3. Somatic mutation analysis demonstrated loss of heterozygosity of FH in 10 tumours. Copy number variation analysis revealed uniparental disomy between 1q24.2 and 1q44 encompassing FH; gain of chromosome 2 p was also common. All patients had either metastases or residual tumours. Three patients died of HLRCC-RCC and one of colon cancer, whereas the other six are currently alive, including two without recurrence.ConclusionsHLRCC-RCCs appear to have unique molecular profiles, including PD-L1 expression. One patient had complete response to immunotherapy, which may be an option for HLRCC-RCC.

Stereotactic body radiotherapy-induced abscopal effect twice after pembrolizumab failure in hereditary leiomyomatosis and renal cell carcinoma: a case report with genetic and immunologic analysis

“…To our knowledge, this is the first case of HLRCC that demonstrated an unexpectedly good response to ICI-based cases; PD-L1 expression ≥30%), high expression of PD-L1 was also observed in our HLRCC case (5,6). She achieved PR on ICI-based therapy and her lesions were controlled for 20 months; consistent with the observation by Sun et al who found that for FH-deficient metastatic renal cell carcinoma patients receiving ICIs based therapy (n=6), their median PFS was significantly longer than those treated with antiangiogenic monotherapy (n=12) (13.3 vs. 5.1 months) (6).…”

“…Recently, two small sample-sized (n=10 and n=16) studies reported high positivity (80-90%) of PD-L1 expression in HLRCC; suggesting the potential application of immune checkpoint inhibitors (ICIs) (5,6). As a boost to improve immunotherapeutic outcomes, stereotactic body radiotherapy (SBRT) has been suggested as an ideal partner in some solid tumors (7,8).…”

A novel pathogenic variant of the FH gene in a family with hereditary leiomyomatosis and renal cell carcinoma

“…Specifically, the wild-type allele was lost, and the germline variant was retained. The occurrence of such an LOH event in the FH gene, which is frequently observed in HLRCC-associated RCC 11 , would be of substantial importance, thereby confirming that Knudson’s two-hit theory for tumor suppressor genes can be applied to FH . Of note, the minor existence of the wild-type allele in the tumor (Fig.…”

Germline Whole-Gene Deletion of FH Diagnosed from Tumor Profiling

“…Several previously reported Japanese families with HLRCC exhibited different pathogenic variants, including missense variants and a splice site variant that had not been reported in Caucasian families [ 18 , 19 , 20 , 21 , 22 , 23 ]. To the best of our knowledge, ours is the first report of a whole-gene FH deletion in Japan.…”